Chemical bilology research blogging

Okay, so here's a little example of the kind of chemical biology that I am not convinced has a point for biology, it seems much more self-serving for famous chemists to indulge their 'we made this complicated thing in an extremely complicated way' obsession.

On the one hand, I read this essay by Tom Muir, which is totally SPOT ON about the future of chemical biologists as functional members of the research society. He's been one of the pioneers of this new cross-branching, so it makes sense he would know what is going on.

Then there was this. Three papers came out in the recent issue of JACS, all from the same research group (very famous) and all in a row. They all seem to contain the same authors but in different orders, all full articles. They all focus on making various parts of a fully synthetic, homogenously glycosylated EPO. They use phrases like 'Our venture commenced with the preparation of' and 'Several strategies were entertained' and this doozy: 'difficultly predictable conformation' (emphasis mine to highlight the typical chemist way with words). They also spend valuable page space (and reader time) expounding on how they tried this or that method that didn't work but fortunately such and such other method did, and detailing every little aspect of every single specific reaction including rapidity of consumption of starting material, and how happy they were about that. It ends up sounding seriously medieval.

They try to lay it all out old-fashioned-style like this is some kind of hypothesis driven research into a general glycoprotein synthesis strategy that will somehow revolutionize the field of 'biologics,' rather than the ponderous, author-heavy, complex target-based total synthesis it actually is. Yes, maybe a homogenously glycosylated EPO would be useful for figuring out which glycoforms have particular biological effects. But these (not one, not two but three, count 'em) THREE papers don't clearly highlight any generality or modularity that could be used for any glycoprotein. Their side chains are covered with protecting groups. They don't demonstrate how you could easily clip on any homogenous carbohydrate modification to relevant sites. Nor do they describe some new jump in efficiency of synthesis, or a new exquisitely-selective and exciting reaction (they just use minor modifications of existing strategies). These are the kinds of things that would be necessary to address their proposed justification that these methods could revolutionize drug discovery for biologics.

They don't appear to have a biological collaborator who might be able to make sure they are pointed in a useful direction, and regardless of their repeated assertions that the biological impact of their project is so lofty, as a chemical bilologist, nascent cell physiologist and protein chemist, I'm just not seein' it. This looks more like a classic case of misguided synthetic hubris combined with author-laundering to maximize publication number. I understand that students and postdocs want to get their first-author paper on the thing they made, but it really dilutes the report of the research unnecessarily to split up a common project in this way. This could have been one paper simply and clearly showing the synthesis of the three segments and that's it. That's all that is here. Or better yet, wait until you actually MADE the full EPO and publish ONE paper on it. We don't need to hear the stream of consciousness/chronological story of your trevails. We just want to know if you did something important.

They say at the end of the final paper that they expect to be able to use their fragment condensation strategy with the understanding that "with all complex target oriented total synthesis, intervention of the unexpected is predictable. That being said, we are hopeful that the convergent nature of our synthesis and its flexibility will enable its adaptation to reach our goals." Good, I'm glad they are hopeful!! It's much better than being depressed about how your long, long, tenuously important project is not changing anything significant about protein chemistry!

This is the kind of thing that bothers me about the divide between old-school and new-school chemistry. Young chemists are being misled into thinking this kind of thing has impact. They are not looking at these problems with biologists asking them critical questions all along the way (nor asking those critical questions of themselves). Ultimately, they are wasting a lot of their time on directions that could be much better informed by understanding how and why things like this might be useful, and the real requirements for making them so. I just don't understand why people still keep doing stuff like this.

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